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A LC–MS/MS method was established for QX-OH measurement.The method is simple, sensitive, reliable and meets all the validation criteria.The first method for determination of local anesthetic in muscle and sciatic nerve.Low injection volume (3–4 μL) and short run time (≤5 min).The method was successfully applied to pharmacokinetic study of QX-OHQX-OH, a new synthetic local anesthetic, produced concentration-dependent, reversible, and long-acting local anesthesia in animal models, with moderate local toxicity. As part of preclinical research for drug development, we developed and validated a method for the determination of QX-OH in the plasma, muscle, and sciatic nerve using liquid chromatography–mass spectrometry. After a simple protein precipitation procedure, analysis was performed on an Extend C18 column (100 mm × 3 mm, 3.5 μm) by isocratic elution with 0.05% formic acid/acetonitrile (78:22, v/v) at a flow rate of 0.3 mL/min. A multiple-reaction monitoring mode at the transitions of m/z 279.1 → 102.1 for QX-OH and m/z 275.2 → 126.1 for an internal standard (ropivacaine hydrochloride) was used for the quantification, with a positive electrospray ionization interface. The approach was validated as per the U.S. Food and Drug Administration guidelines and successfully used in a pharmacokinetic study of QX-OH after a sciatic nerve block with 0.2 mL of 35 mM QX-OH. The results demonstrated that the new local anesthetic, QX-OH, had a high concentration in tissue, low systemic exposure, and long duration in the sciatic nerve.